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P1: SFK/UKS P2: SFKc09 BLBS044-Cho October 12, 2009 19:40 Printer Name: Yet to Come
CHAPTER 9
Soy Peptides and WeightManagement
Cristina Martınez-Villaluenga, PhD, and Elvira Gonzalezde Mejıa, PhD
Abstract
In this chapter, the authors relay available scientific information regarding therole of soy peptides or soy hydrolysates on weight management. Proposed mech-anisms include (a) regulation of satiety and food intake; (b) decrease lipid absorp-tion and modulation of lipid metabolism; (c) increased thermogenesis and energyexpenditure; and (d) inhibition of adipogenesis. Although there is not enoughclinical information to claim a clear benefit of soy peptides on obesity, there is ev-idence to suggest that some soy peptides may have a future as regulators of adipos-ity and satiety. These two properties may have an impact on weight management.
Introduction
Obesity is a major contributor to the burden of chronic disease anddisability in developed and developing countries. Despite public healtheducation, the prevalence of obesity continues to increase and more than30% of adults in the United States are obese (Odgen et al., 2007). Theuse of most drugs developed to date is limited by unacceptable adversereactions or the potential for abuse during long-term pharmacotherapy(Ioannides-Demos et al., 2006). Therefore, new therapeutics to reducebody weight with minimal adverse reactions will be beneficial. In recentyears, high-protein diets gained widespread popularity before scientific
135Weight Control and Slimming Ingredients in Food Technology Susan S. Cho© 2010 Blackwell Publishing. ISBN: 978-0-813-81323-3
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136 Protein based ingredients
Dietary proteins
Intestinal tract Inside the bodyEpithelial cells
Proteins
Peptides
Peptides andamino acids
Hydrolyzed
Hydrolyzed
Metabolized
Di(tri)peptides
Amino acids
Proteinases
Oligopeptides
Peptidases
Di(tri)peptides
Peptidases
Amino acids Amino acids
Resistantdi(tri)peptides
Resistantoligopeptides
Resistantdietary proteins
Figure 9.1. Bioactive peptides are liberated from dietary proteins and candisplay bioactivity in the small and large bowel (Adapted from Shimizu,2004.)
evidences on their safety or efficacy were fully understood. Dietary pro-teins are hydrolyzed to amino acids and peptides in the gastrointestinaltract, and consequently different chain lengths and amino acid sequencesare generated as intermediates. Figure 9.1 presents a simplified diagramof the absorption of food-derived peptides. These peptides have impor-tant roles in the intestinal tract before being absorbed because they canmodulate nutrient absorption in the intestines. The understanding of theperformance of dietary peptides in the intestine is vital for designingfunctional foods with physiological functions (Shimizu, 2004).
Peptides are absorbed directly from the intestine by peptide-specifictransport systems (Takamatsu, 2006). A peptide-specific transporter wascloned and characterized as a H+-coupled transporter of oligopeptidesnamed PepT1 (Fei et al., 1994). It displays broad substrate specificity,unlike amino acid transporters. These studies clearly show that peptidesare absorbed with their intact primary structures (Chun et al., 1996; Iharaet al., 1990). Thus, it is thought that in the intestine, peptide transportersconstitute a major mechanism for absorption of the products of proteindigestion (Brandsch et al., 2008; Fei et al., 1994).
Peptides are unique components of living organisms and appear inmany biological capacities, nutritional activities, and fermentation pro-cesses. Many types of biologically active peptides in the body, such as hor-mones, participate in inter- and intracellular communication and activities.
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Soy Peptides and Weight Management 137
Research to determine the physiological function of dietary peptides, andthus their health benefits, are markedly increasing. Recent in vitro and invivo studies have shown that, in addition to soy protein and isoflavones,peptides derived from soy protein have biological activities against obe-sity through different mechanisms. To be considered “bioactive,” a dietarypeptide should impart a measurable biological effect at a physiologicallyrealistic level and this “bioactivity” has to have the potential to positivelyaffect health (Moller et al., 2008).
Processing methods using enzymes, acids, and heating are used for pro-tein hydrolysis to produce peptides. In particular, enzyme hydrolysis hasthe advantage of high-sequence specificity, low energy cost, and avoidanceof generating undesirable compounds. Soy peptides may be also producedby fermentation of soybean in which protein hydrolysis takes place bymicrobial proteases. This is a suitable method of producing soy peptidesfor food applications, especially for health purposes.
In this chapter, we provide an overview of the most up-to-date ex-perimental evidence on efficacy, mechanisms of action, safety, and foodapplications of soy peptides in weight management.
Efficacy and Mechanisms of Action of SoyPeptides in Weight Management
A number of studies in cell lines, animals, and humans support theevidence concerning the potential relationship between soy peptides andweight loss. The mechanisms whereby soy peptides have an impact onweight loss are still under study. Several lines of evidence suggest that soypeptides may affect satiety and food intake (Foltz et al., 2008; Jang et al.,2008; Nishi et al., 2003a, 2003b; Rho et al., 2007; Takenaka et al., 2000b),lipid absorption and lipid metabolism (Aoyama et al., 2000a; Cho et al.,2007; Jang et al., 2008; Lovati et al., 2000; Takenaka et al., 2000a; Yanget al., 2007), energy expenditure and thermogenesis (Claessens et al., 2007;Vaughn et al., 2008), and inhibition of adipogenesis (Kim, 2007; Kimet al., 2007). Table 9.1 summarizes the antiobesity effects and proposedmechanisms of action for soy peptides/hydrolysates.
Soy Peptides May Help Weight Controlby Suppressing Food Intake
It is believed that the mechanism of action of soy peptides is to regu-late food intake by inducing satiety through the activation of opioid and
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Tab
le9.
1.A
ntio
besi
tyef
fect
san
dpo
tent
ialm
echa
nism
sof
actio
nre
port
edfo
rso
ype
ptid
es/h
ydro
lysa
tes
Mat
eria
lP
repa
rati
onM
echa
nism
ofA
ctio
nR
efer
ence
β-C
ongl
ycin
inpe
ptid
esan
dhy
drol
ysat
es
Synt
hesi
s;hy
drol
ysis
bype
psin
pH1.
8an
dtr
ypsi
npH
8.0
at37
◦ Cfo
r10
min
utes
Supp
ress
ion
offo
odin
take
thro
ugh
stim
ulat
ion
ofC
CK
1R
and
secr
etio
nof
CC
Kin
vivo
Nis
hiet
al.
(200
3a)
β-C
ongl
ycin
inhy
drol
ysat
esPe
psin
hydr
olys
isat
pH1.
8,37
◦ Cfo
r10
min
utes
Supp
ress
ion
offo
odin
take
thro
ugh
secr
etio
nof
CC
Kan
din
hibi
tion
ofga
stri
cem
ptyi
ngin
vivo
Nis
hiet
al.
(200
3b)
β-C
ongl
ycin
inhy
drol
ysat
esβ
-Con
glyc
inin
hydr
olys
isby
alca
lase
from
B.l
iche
nifo
rmis
atpH
8.0,
50◦ C
for
3ho
urs
Inhi
bitio
nof
lipid
accu
mul
atio
nan
dad
ipon
ectin
indu
ctio
nin
3T3-
L1
adip
ocyt
esK
im(2
007)
Bla
ckso
ype
ptid
esSy
nthe
sis;
prot
ease
hydr
olys
isfo
r5
hour
sSu
ppre
ssio
nof
food
inta
keth
roug
hle
ptin
-lik
esi
gnal
ing
inth
ehy
poth
alam
usin
rode
nts
Jang
etal
.(2
008)
,Rho
etal
.(20
07)
Bla
ckso
ype
ptid
esB
lack
soyb
ean
prot
ein
hydr
olys
isby
prot
ease
for
5ho
urs
Lip
idlo
wer
ing
effe
ctth
roug
hac
tivat
ion
ofth
eph
osph
oryl
atio
nof
5′ AM
P-ac
tivat
edpr
otei
nki
nase
(AM
PK)
and
inhi
bitio
nof
AC
Cph
osph
oryl
atio
nin
rats
Jang
etal
.(2
008)
Bla
ckso
ype
ptid
e(I
le-G
ln-A
Sn)
Bla
ckso
ybea
nhy
drol
ysis
bypr
otea
sefo
r5
hour
s;ul
trafi
ltrat
ion
(MW
CO
3an
d10
kDa)
,gel
filtr
atio
nch
rom
atog
raph
yan
dR
P-H
PLC
Inhi
bitio
nof
adip
ogen
esis
in3T
3-L
1pr
eadi
pocy
tes
Kim
etal
.(2
007)
Pept
ide
from
prog
lyci
nin
A1a
B1b
(LPY
PR)
Try
ptic
–chy
mot
rypt
icdi
gest
ion
ofge
netic
ally
mod
ified
prog
lyci
nin
Supp
ress
ion
offo
odin
take
Take
naka
etal
.(2
000b
)
Pept
ide
from
glyc
inin
A5A
4B
3
(LPY
PR)
Try
ptic
–chy
mot
rypt
icdi
gest
ion
ofgl
ycin
inA
5A
4B
3
Lip
idlo
wer
ing
effe
ctby
redu
cing
chol
este
rola
bsor
ptio
nan
din
crea
sing
feca
lbi
leex
cret
ion
Take
naka
etal
.(2
000a
)
138
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Soy
prot
ein
hydr
olys
ate
Soy
prot
ein
isol
ate
hydr
olys
isby
prot
ease
from
Bac
illu
ssu
btil
lis
(Hyn
ute-
D1)
Lip
idlo
wer
ing
effe
ctby
redu
cing
chol
este
rola
bsor
ptio
nan
din
crea
sing
feca
lbi
leex
cret
ion
inm
ice
Aoy
ama
etal
.(2
000a
)
Soy
prot
ein
hydr
olys
ate
Soy
prot
ein
conc
entr
ate
(Cro
ksoy
R70
)hy
drol
ysis
bype
psin
-try
psin
;ultr
afiltr
atio
nus
ing
cuto
ffm
embr
anes
of3,
000
and
1,00
0kD
a
Cho
lest
erol
low
erin
gef
fect
;red
uced
synt
hesi
sof
intr
acel
lula
rch
oles
tero
lby
upre
gula
tion
ofL
DL
-Rtr
ansc
ript
ion
inhu
man
liver
cell
line
Lov
atie
tal.
(200
0)
Soy
prot
ein
hydr
olys
ates
Isol
ated
soy
prot
ein
hydr
olys
isby
alka
line
(APR
68)
and
neut
ralp
rote
ase
(NPR
68)
from
B.a
myl
oliq
uefa
cien
sFS
E-6
8
Cho
lest
erol
low
erin
gef
fect
;red
uced
synt
hesi
sof
intr
acel
lula
rch
oles
tero
lby
upre
gula
tion
ofL
DL
-Rtr
ansc
ript
ion
inhu
man
liver
cell
line
Cho
etal
.(2
007)
Soy
prot
ein
hydr
olys
ate
Soyb
ean
acid
-pre
cipi
tate
dpr
otei
nhy
drol
ysis
bype
psin
atpH
2,37
◦ Cfo
r24
hour
s
Dec
reas
elip
idac
cum
ulat
ion
inth
eliv
eran
dhy
polip
idem
icef
fect
sby
enha
ncin
gex
cret
ion
and
inhi
bitin
gab
sorp
tion
oflip
ids
inra
ts
Yan
get
al.
(200
7)
Soy
prot
ein
hydr
olys
ates
Dri
nks
cont
aini
ngso
ypr
otei
nhy
drol
ysat
e(0
.4g
prot
ein
hydr
olys
ate
per
kgof
body
wei
ght)
Incr
ease
ofen
ergy
expe
nditu
rean
dth
erm
ogen
esis
inhu
man
sC
laes
sens
etal
.(20
07)
Soy
prot
ein
hydr
olys
ates
Soy
prot
ein
isol
ate
hydr
olys
isby
alca
lase
from
B.l
iche
nifo
rmis
atpH
8,50
◦ Cfo
r3
hour
s
Inhi
bitio
nof
adip
ogen
esis
thro
ugh
over
expr
essi
onof
pref
-1fa
ctor
in3T
3-L
1pr
eadi
pocy
tes
Kim
(200
7)
Soy
prot
ein
hydr
olys
ates
Que
stIn
tern
atio
nal,
The
Net
herl
ands
Supp
ress
ion
offo
odin
take
thro
ugh
stim
ulat
ion
ofC
CK
1R
and
secr
etio
nof
CC
Kin
vitr
o
Foltz
etal
.(2
008)
Soy
prot
ein
hydr
olys
ates
Soy
prot
ein
isol
ate
hydr
olys
isby
alca
lase
from
B.l
iche
nifo
rmis
atpH
8,50
◦ Cfo
r3
hour
s
Red
uctio
nof
body
wei
ghta
ndfo
odin
take
byin
crea
sing
ener
gyex
pend
iture
and
ther
mog
enes
isin
rats
Vau
ghn
etal
.(2
008)
139
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140 Protein based ingredients
cholecystokinin (CCK) receptors in the gut (Pupovac and Anderson, 2002).In vitro studies support the evidence that soy peptides increase markersof satiety and reduce energy intake, which directly may impact weightloss. Foltz et al. (2008) demonstrated that soy hydrolysates (Quest Inter-national, The Netherlands) at low concentrations (10 mg/L) stimulatedthe release of satiety hormones such as CCK from STC-1 enteroendocrinecells up to 2.1-fold, which in turn activated CCK1 receptor (CCK1R).Furthermore, soy hydrolysates stimulated CCK1R-expressing cells andmay mediate satiety at least in part, by direct receptor stimulation. Insummary, this study demonstrated the potential importance of selectedshort-chain peptides to act in a dual mode on dietary satiety signaling.In another investigation, in vivo intraduodenal infusion of β-conglycininhydrolysates inhibited food intake of rats in a dose-dependent manner andthis suppression was abolished by intravenous injection of devazepide, aselective peripheral CCK receptor antagonist (Nishi et al., 2003a). Thearginine residues in the protein structure was shown to be responsiblefor CCK release through direct action on the intestinal cells. Regardingthe relationship between arginine and binding activity to brush bordermembrane, synthetic model peptides with one arginine (GGGRGGG andGGGGGGR) showed no activity. The binding activity of synthetic pep-tides containing two arginine residues depended on the position of thearginine residues. GGRGRGG, GRGGRGG, and GRGGGRG can bindto the brush border membrane while GGGRRGG cannot. GRGRGRG, asynthetic peptide containing three arginine residues had stronger bindingability (Nishi et al., 2003b). Comparing several arginine fragments of β-conglycinin on their abilities to bind to the intestinal cell component, thefragment from 51 to 63 of the β subunit of β-conglycinin was found tohave the highest binding affinity, also affecting food intake in rats (Nishiet al., 2003b). Soybean β-conglycinin pepsin hydrolysates not only sup-pressed food intake but also inhibited gastric emptying by direct actionon CCK secretion, which contributed to reduction of food intake (Nishiet al., 2003b).
Other in vivo studies demonstrated the potential antiobesity activity ofa novel peptide mixture called black soy peptide (BSP) derived from blacksoybean (Jang et al., 2008; Rho et al., 2007) through leptin-like signalingin the hypothalamus. This peptide mixture did not contain a significantamount of isoflavones, and small-size peptides (<10 Kda) composed ofmore than 80% of BSP. Short- and long-term effects of BSP were evalu-ated in induced obese rodents fed a high-fat (HF) diet without or with BSP(2%, 5%, and 10% of energy) for 4 weeks (Rho et al., 2007), 13 weeks,or 8 weeks in combination with exercise (Jang et al., 2008). Rodents fed
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Soy Peptides and Weight Management 141
an HF diet with BSP (2%, 5%, or 10%) for 4 or 13 weeks gained lessbody weight than rodents fed HF diet without BSP, concurrent with in-hibition of total food intake in a dose-dependent manner. In addition, theantiobesity and fat reduction effects of black soy protein increased whencombined with low-intensity exercise. Jang et al. (2008) could detect aspecific hepta-peptide (IPPGVPY in BSP at 50 µg/g) in plasma at 30 min-utes after oral administration of BSP (1 g) in rats, suggesting that peptidesin the BSP mixture might be absorbed as intact molecules. Body weightregulation of BSP has been related to a major signaling pathway such asJAK2-dependent STAT3 activation (Jang et al., 2008). The leptin-mediatedSTAT3 phosphorylation pathway in the hypothalamus is a major cellularmechanism among the multiple pathways involved in suppressing food in-take and promoting energy expenditure (Bates and Myers, 2003; Spiegel-man and Flier, 2001). Induction of hypothalamic STAT3 phosphorylationby BSP was demonstrated in leptin-deficient ob/ob mice, suggesting thatanorectic effect of soy peptides is through leptin receptor and activationof leptin-like signaling in the hypothalamus at a concentration as lowas 1 µg/mL.
Some anorectic peptides have been also identified to exert antiobesityactivity through decreasing food intake, fat body mass, and body weight.One example is a Leu-Pro-Tyr-Pro-Arg peptide from soybean glycininA5A4B3 subunit (Takenaka et al., 2000a, 2000b).
Soy Peptides May Reduce Adiposityby Inhibiting Lipid Absorption and Regulationof Lipid Metabolism
There is in vivo evidence that consumption of soy peptides can re-duce serum total cholesterol, LDL cholesterol, and triglycerides as well ashepatic cholesterol and triglycerides (Aoyama et al., 2000a, 2000b; Choet al., 2007; Jang et al., 2008; Takenaka et al., 2000a; Yang et al., 2007).Studies in animals indicate that soy peptide ingestion exerts its lipid low-ering effect by reducing intestinal cholesterol absorption and increasingfecal bile acid excretion, thereby reducing body fat accumulation, hep-atic cholesterol content, and enhancing removal of LDL (Aoyama et al.,2000a, 2000b; Takenaka et al., 2000a). Yang et al. (2007) demonstratedthe hypolipidemic effects of nondialyzed soy protein hydrolysate (NSPH)in rats fed a cholesterol-rich diet. After a 12-week experimental period,the NSPH groups had a significant lower plasma concentration of totalcholesterol, triglycerides, and LDL-cholesterol compared with the casein
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142 Protein based ingredients
group. Moreover, fecal excretion of neutral steroids and nitrogen com-pounds was significantly higher in NSPH group than that in the caseingroup. An in vitro study also showed that NSPH, compared with ca-sein, decreased cholesterol micellar solubility. These results suggestedthat NSPH may decrease lipid accumulation in the liver and have a hy-polipidemic effect by enhancing excretion and inhibiting absorption oflipids.
Some studies have demonstrated the effectiveness of feeding mixturescontaining soy peptides, l-carnitine, and Garcinia cambogia extract onbody weight and lipid metabolism in obese rats fed a HF diet (Kimet al., 2005; Park et al., 2006). Results suggested that this mixture waseffective in reducing body and adipose tissue weight, probably due tothe modulation of lipid metabolism and the increased fecal excretionof lipids. Kim et al. (2003) investigated the effect of combination of afunctional beverage (containing Garcinia cambogia 300 mg, l-carnitine20 mg, and soy peptides 1,000 mg) and exercise in body composition andbiochemical metabolic profile in humans. Eighty-one healthy volunteers(69 females aged 19–50 years and 12 males aged 19–55 years), who main-tained their body weight stable at 23 or higher BMI and 25% or higherbody fat for the past 3 months, were recruited for the study. The researchdesign was a randomized, double-blind, placebo-controlled parallel groupdesign. All participants were given 12-week programmed-exercise, whichwas performed three times a week. One bottle (100 mL) of test or placebosolution was given daily, 30 minutes before each session of programmedexercise. At the end of 4, 8, and 12 weeks, approximately 2.0%, 3.0%, and3.5% losses of body weight were observed, respectively, in the test group(p < 0.01) and 0.3% 0.7%, and 1.6%, respectively, in the placebo group(p > 0.05). In conclusion, the combination of the functional beverage,which contained Garcinia cambogia, l-carnitine and soy peptides, andexercise had a synergistic effect on reducing body fat.
Dietary soy peptides have also been shown to directly affect hepaticcholesterol metabolism and LDL receptor activity. Lovati et al. (2000)demonstrated in vitro that trypsin plus pepsin CroksoyR70 peptides, with-out isoflavone components, showed a marked upregulation of LDL re-ceptor versus controls. Similarly, Cho et al. (2007) demonstrated that soypeptides can effectively stimulate LDL-R transcription, in a human livercell line, and that dietary upregulation of the LDL-R transcription by soy-bean may be consequent to an enhanced catabolism or a reduced synthesisof intracellular cholesterol. Soy oligopeptide mixtures (200–5,000 Da)have also been shown to be useful as apolipoprotein B (Apo B), the struc-tural protein of LDL secretion inhibitors in HepG2 cells, for treatment of
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Soy Peptides and Weight Management 143
obesity and other lifestyle diseases. Based on these results, a storage-stable beverage containing this mixture in freeze-dried powder form wasalso formulated (Inoue et al., 2004).
Jang et al. (2008) demonstrated that BSP may have an impact in bodyweight and hypotriglyceridemic effect through activation of the phospho-rylation of 5′AMP-activated protein kinase (AMPK) followed by acetyl-CoA carboxylase (ACC) phosphorylation inhibition. AMPK functions asa sensor of the intracellular energy state and is activated by exercise,adiponectin, leptin, and sympathetic outflow (Carling, 2004). A long-termdietary soy peptides intervention study significantly increased plasmaadiponectin when mice were fed high doses of BSP (10%) in the diet.Adiponectin has received attention because it decreases the concentrationof plasma triglycerides and free fatty acids primarily through the activationof AMPK (Yoon et al., 2006). In skeletal muscle cells, activated AMPKincreases fatty acid oxidation through the influx of long-chain fatty acidsinto the mitochondria.
Soy Peptides May Reduce Body Weightby Increasing Energy Expenditureand Thermogenesis
Increased postprandial thermogenesis results in greater energy utiliza-tion, which in turn may contribute to a reduction in body weight. Proteins,including soy hydrolysates, have a higher postprandial thermic effect thancarbohydrates or fat and therefore could be more effective in weight re-duction. Vaughn et al. (2008) investigated the effect of soy hydrolysateson body weight and food intake in adult rats receiving intracerebroventric-ular injections of soy hydrolysates (100 µg/ µL) three times weekly for 2weeks. The hydrolysates caused a significant body weight reduction (p <
0.001) without reducing food intake. It was speculated that peptides in thesoy hydrolysate may act by mechanisms that regulate energy metabolismand thermogenesis. A main reason for the difference in the thermic effectsof foods higher in protein compared with those higher in carbohydrates orfats may be attributable to the fact that the body has no storage capacityfor protein, and thus it needs to be immediately metabolically processed(Hu, 2005). The synthesis of proteins, the high ATP cost of peptide bondsynthesis, and the high cost of urea production and gluconeogenesis arepossible reasons for the higher thermic effect of protein (Mikkelsen et al.,2000; Robinson et al., 1990).
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144 Protein based ingredients
The interaction between the consumption of soy protein hydrolysatesand carbohydrates on thermogenesis and hormonal secretion has alsobeen tested. Claessens et al. (2007) reported the effect of soy proteinhydrolysates, with and without a carbohydrate pre- and afterload, onenergy metabolism and hormonal secretion in eight healthy nonobesesubjects. In all cases, 0.4 g protein and/or carbohydrate per kilogram ofbody weight were tested. Soy hydrolysate consumption led to a higherdiet-induced thermogenesis than a carbohydrate load. Thermogenesis in-duced by soy protein hydrolysate combined by a carbohydrate pre- orafterload also increased energy expenditure. The larger diet-induced ther-mogenesis, after protein consumption than after carbohydrate, may berelated to the glucagon response that is induced by protein but not bycarbohydrates. Glucagon is a regulatory response to hypoglycemia. Inthis regard, glucagon stimulates glucose output by increasing liver gly-coneolysis and gluconeogenesis (Jiang and Zhang, 2003), and insulin.Furthermore, when soy protein hydrolysate consumption was followedby a carbohydrate load, it did not result in a rise in plasma glucose con-centration. This may be probably due to the fact that peptides elevatedplasma insulin levels before the carbohydrate load consumption. There-fore, soy peptides ingestion may have other additional health benefits aspreventing plasma glucose increase when carbohydrates are ingested afterproteins.
The relative contribution of fat and carbohydrates on postprandial en-ergy expenditure when consuming soy protein has been investigated inexperimental animals. Ishibara et al. (2003) compared the effects of feed-ing a soybean peptide isolate diet on the oxidation of dietary carbohydrateand lipids in type II diabetic mice. When diabetic mice were fed a restricteddiet, postprandial energy expenditure was higher in the soy peptide groupthan in the casein group. The authors suggested that the difference in en-ergy expenditure between the groups was due to an increase in postprandialcarbohydrate oxidation promoted by the soybean peptide.
Soy Peptides May Reduce Adiposity throughInhibition of Adipogenesis
Adipogenesis is a process through which a fibroblast, first becomes apreadipocyte, then a multilocular adipocyte, and, finally, a mature (uniloc-ular) adipocyte (Fernyhough et al., 2005). During the maturation processof adipocytes, the increase in lipid mass caused by increase in size ofadipocytes is termed hypertrophy. Hypertrophy in adipose tissue occurs
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Soy Peptides and Weight Management 145
in response to weight gain due to excess calorie intake. Increase of bodyweight produces increase in number of adipocytes termed as hyperplasia.There are limited data from in vitro experiments analyzing the specificeffects of soy peptides on adipose tissue development (adipogenesis).Results from our laboratory showed the effectiveness of soy peptideson adipogenesis including proliferation of preadipocytes, hypertrophyof adipocytes, expression of preadipocyte factor-1 (pref-1), adiponectin,and lipid accumulation using the Swiss mouse 3T3-L1 cell line as amodel (Kim, 2007). Preadipocytes and mature adipocytes were incu-bated with soy protein isolate hydrolysate (SH), β-conglycinin hydrolysate(BCH), and commercial purified soy peptides (SPP). Figure 9.2 presentsthe inhibitory effect of soy products on proliferation of preadipocytes.Hydrolyzed β-conglycinin (BCH) inhibited preadipocytes in a dose-dependent manner (IC50, 455 µM) (Fig. 9.2a). Alcalase-hydrolyzed soyprotein isolate (SH) also showed a clear dose response (IC50, 700 µM)
AB
C
A
BC
B
C
25
–0.5 0.0 0.5
Log (µM)(a)
(b) (c)
0.25–10292 583 11670
1020
Inhi
biti
on (
%)
304050607080
100
20Inhi
biti
on (
%)
304050607080
1.44 2.52
mMµM
4.66 6.99
1.0 1.5 2.0
50
75
Inhi
bitio
n (%
)
100
Figure 9.2. Inhibitory effect of soy hydrolysate products on preadipocyte pro-liferation measured by cell viability MTS assay after 72 hours of treatment. (a)Inhibitory effect of alcalase-hydrolyzed β-conglycinin (BCH), IC50 = 455 µM.(b) A dose-response inhibitory effect of alcalase-hydrolyzed soy protein isolates(SH), IC50 = 700 µM (c) A dose-response inhibitory effect of soy-purified pep-tides (SPP), IC50 = 2.3 mM (different letters indicate significant differences, p <
0.05). Error bars indicate standard deviation.
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146 Protein based ingredients
0.0
0.5
1.0
1.5
2.0
2.5
3.0
SPP SH
Fol
d in
crea
se p
ref-
1 ve
rsus
con
trol
A
B
Figure 9.3. Fold increase in pref-1 (60 kDa) by soy-purified peptides (SPP, 2.3mM) and alcalase soy hydrolysates (SH, 700 µM).
(Fig. 9.2b). Figure 9.2c shows the inhibitory effect by SPP (IC50, 2.3 mM).In our study, it was found that β-conglycinin hydrolysate showed thehighest inhibition of preadipocyte proliferation with the least amount ofprotein, which implied that this protein may have a key role in adipogen-esis.
Figure 9.3 presents the increase in the expression of pref-1 (60 kDa), inpreadipocytes exposed to IC50 values of SPP (2.3 mM), SH (700 µM), for72 hours in comparison to their controls. Several biomarkers are involvedduring adipogenesis and some are specific to preadipocytes, which includepref-1. Pref-1 is a regulator of adipogenesis due to its role in adipocytedifferentiation (Wang et al., 2006). Pref-1 is a transmembrane protein of385 amino acids (60 kDa) that can exist in multiple membrane forms.Overexpression of pref-1 is known to decrease fat mass, reduce expres-sion of adipocyte markers, and lower adipocyte-secreted factors, such asadiponectin (Lee et al., 2003).
Figure 9.4 presents the evaluation of lipid accumulation and adiponectinexpression in 3T3-L1 adipocytes treated with β-conglycinin hydrolysates.Adiponectin is a 30 kDa protein composed of 244 amino acids and is oneof the adipocytes-specific hormones (Maeda et al., 1996). Adiponectinimproves insulin sensitivity and regulates metabolism of lipids and glucose(Berg et al., 2001; Druce et al., 2004). Several studies have found thatinduction of adiponectin decreases body weight, plasma triglycerides, andfatty acid oxidation (Nedvidkova et al., 2005; Qi et al., 2004; Yamauchiet al., 2003). The most interesting aspect of this hormone is that its leveldecreases in an obese individual and, thus, its absence is closely related toobesity (Buemann et al., 2006; Hu et al., 1996).
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Soy Peptides and Weight Management 147
0.0
0.5
1.0
1.5
2.0
2.5
Beta-conglycinin hydrolysate
Ad
ipo
nec
tin
exp
ress
ion
(fo
ld in
crea
se v
s. c
on
tro
l) 10 µM 100 µM
0
10
20
30
40
50
60
Beta-conglycinin hydrolysate
Lip
id a
ccu
mu
lati
on
inh
ibit
ion
(%
)ve
rsu
s co
ntr
ol
10 µM 100 µM
(a) (b)
Figure 9.4. β-conglycinin hydrolysates inhibit lipid accumulation (a), and in-duce adiponectin expression (b) in 3T3-L1 adipocytes. Error bars indicate standarddeviation.
In summary, soy hydrolysates have the capacity to inhibit in vitro adi-pogenesis by upregulation of preadipogenic pref-1 factor. In addition, ourdata suggest that β-conglycinin hydrolysate may have an impact on weightloss by induction of adiponectin expression and inhibition of lipid accu-mulation in adipose tissue. In vitro studies are not a direct approach toobesity treatment. However, offering the understanding of the mechanismof action and the potential for in vivo studies may show benefits in themanagement of obesity.
Kim et al. (2007) identified a tripeptide, Ile-Gln-Asn, from black soy-bean hydrolysate as adipogenesis inhibitor in 3T3-L1 preadipocytes, hav-ing IC50 value of 14 µg protein/mL. These results were confirmed with asynthetic tripeptide.
Food Applications of Soy Peptidesfor Weight Control
Based on the antiobesity activity of soy and soy peptides, various foodsand beverages have been developed. For example, a soy protein mealreplacement formula (Scan Diet) has been found effective for weight lossand fat mass reduction in obese subjects (Allison et al., 2003). Otherproducts include antiobesity formulas containing proteins, water-solublefibers and gelatins, mineral, vitamins, and soy peptides (Fujita, 2000; Inoueet al., 2004; Son and Bang, 1999). A sugar-free coffee containing soybean
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148 Protein based ingredients
protein hydrolysate was also developed (Miura, 2002). This beveragecontained oligopeptides with three to six amino acid residues preparedby enzymatic hydrolysis of soybean protein. Ingestion of this kind ofsugar-free coffee for 8 weeks led to a 4–7% body weight reduction inhuman volunteers. Soybean peptides have also been used as body fatdecreasing agents in foods. It has been observed in humans that body fat,serum glycerides and cholesterol can be decreased by peptides withoutdecreasing body proteins (Inaba et al., 2002). Although all these findingsare encouraging, clinical studies are needed to assess the true contributionof soy peptides to weight management.
Current data suggest that soy peptides may have the potential abilityto prevent obesity but results must be carefully interpreted and additionalevidence is needed before making firm conclusions concerning the effectof soy peptides on weight loss. Although soy protein/peptides may beconsidered as good as other protein sources for promoting weight loss,a suggestive body of evidence indicates that soy foods confer additionalbenefits (Cope et al., 2008).
Safety of Soy Peptides
Peptides are normally generated during protein digestion in the gastroin-testinal tract. Because soy hydrolysates and fermented soybean productshave been safely used as food for years without apparent harmful effects,the risk of toxicity caused by peptides formed during these processes ispractically nil. Although peptides can be absorbed into the blood, therehave been no reports about toxic effects of soybean peptides to date.
An additional concern about the safety of proteins is their allegenic-ity. To date, 34 soybean proteins have been identified as allergens (FarrpAllergen Protein Database, 2008; Xiang et al., 2008). However, enzymatichydrolysis is the predominant method for reducing allergenicity of pro-teins. The best examples of food products that are processed to renderthem less allergenic are hydrolyzed infant formulas (FDA, 2005). Songet al. (2008b) showed that hydrolyzed soybean ingredients exhibited neg-ligible IgE immunoreactivity to soy proteins and peptides using differenthuman plasma samples from subjects reporting previous soybean allergies.Soy-hydrolyzed ingredients are produced by means of heat denaturationand/or enzymatic hydrolysis, sometimes in combination with ultrafiltra-tion or high pressure. The additional ultrafiltration step is able to eliminatemost residual immunodominant peptides (Song et al., 2008b). Lee et al.(2007) reported that peptic and chymotryptic hydrolyzed fragments of 11S
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Soy Peptides and Weight Management 149
globulin, of less than 20 kDa, were no immunoreactive to IgE in humanplasma.
Fermentation process has been investigated with regard to its potentialon production of hypoallergenic products (Frias et al., 2008; Song et al.,2008a). Hydrolysis of soy proteins into peptides by microbial enzymesmay undergo destruction of both conformational and linear epitopes, con-sequently reducing or eliminating the antigenicity of soy proteins. Fer-mentation conditions such as particle size, microorganism used, and ex-tent of fermentation may have different impact on reduction of soybeanimmunoreactivity (Frias et al., 2008; Song et al., 2008a). In sum, due tothe production and chemical nature of the peptides, it is highly unlikelythat these products are allergenic.
Information of Global Suppliers
Consumers are becoming more health conscious about the impact oftheir lifestyle and diet on their health. This has resulted in a rapid ex-pansion of the healthy eating market, covering everything from organicthrough more conventional products that are lower in fat, calories, or sugar.Soy-based products include energy bars, soymilk, frozen and refrigeratedmeat alternatives, cold cereal, frozen entrees, cheese and yogurt, cookies,spreads, bread, energy drinks. These products may contain bioactive pep-tides or they can be produced during GI digestion. Some of the productclaims include lower cholesterol, improved gut health, improved immunesystem, improve memory, improve eyesight, and even better complexions.Table 9.2 presents a list of soy products and their suppliers that includesoy peptides in the formulas. Few of them present a health claim re-lated to weight management. More research is needed to find out thebenefits of these peptides added as ingredients to functional foods. Otherapplications may be in dietetic foods, personal care products, fortifiedfoods, dietary supplements among others. Industrial scale production ofhydrolyzed products that would contain peptides are currently in the areasof (a) infant nutrition for easy digestion; (b) clinical nutrition to improveimmune status; and (c) sports nutrition to improve muscle recovery.
Conclusions
Numerous bioactive peptide fragments with different physiological ac-tivities related to obesity have been identified in soy hydrolysates and
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Tab
le9.
2.Pr
oduc
tsth
atco
ntai
nso
ype
ptid
es,s
uppl
iers
,and
heal
thcl
aim
s
Soy
Pro
duct
sSu
ppli
ers
Hea
lth
Cla
ims
Ref
eren
ces
Dai
zuPe
ptid
eN
ysan
kin
(soy
pept
ide
lact
icac
idba
cter
ia),
1,00
0m
gof
soy
pept
ide
Cal
pis-
Ajin
omot
o-D
anon
,Tok
yo,
Japa
nR
egul
ates
GI
cond
ition
san
dre
gain
san
dsu
stai
nsen
ergy
leve
l
Toky
o,Ja
pan
Kar
ada
Mam
eL
atte
Soy
milk
drin
kw
ithso
ype
ptid
esC
alpi
s,Ja
pan
Red
uced
calo
ries
Shib
uya-
ku,T
okyo
,Jap
an
Touc
hi,f
erm
ente
dbl
ack
soyb
ean
extr
act5
5%pr
otei
nC
BC
Co.
Ltd
.,Ja
pan
Impr
ove
met
abol
icsy
ndro
me
(GR
AS
inU
nite
dSt
ates
)
Chu
o-ku
,Tok
yo,J
apan
Pow
erad
eso
ype
ptid
edr
ink,
4,00
0m
gof
soy
pept
ide
Coc
aC
ola
Japa
n,To
kyo,
Japa
nw
ww
.coc
acol
ajap
an.c
o.jp
Dou
Dou
CH
Usw
eete
ned
blac
kso
ym
ilkad
ded
with
soy
pept
ides
2.0
gpr
otei
n/10
0g
Dou
Dou
Chu
,Bei
jing,
Chi
naN
otsp
ecifi
edB
eijin
g,C
hina
Soy
olig
opep
tides
Hez
eR
ocIn
tern
atio
nalC
o.,L
td.,
Chi
naN
otsp
ecifi
edht
tp://
duqi
ng.e
n.ec
plaz
a.n
et
Soy
pept
ide
soy
milk
fort
ified
with
1,80
0m
gof
soy
pept
ide
Kib
unFo
odC
hem
iha,
Toky
o,Ja
pan
Not
spec
ified
ww
w.k
ibun
fc.c
o.jp
Cal
pis-
Mo-
ichi
doso
ype
ptid
edr
ink
Kib
unFo
odC
hem
iha,
Toky
o,Ja
pan
Not
spec
ified
ww
w.k
ibun
fc.c
o.jp
Sapp
le-D
aizu
Pept
ide,
amin
oac
id5,
900
Kib
unFo
odC
hem
iha,
Toky
o,Ja
pan
Not
spec
ified
ww
w.k
ibun
fc.c
o.jp
Fine
-soy
pept
ide
supp
lem
ent
Kib
unFo
odC
hem
iha,
Toky
o,Ja
pan
Not
spec
ified
ww
w.k
ibun
fc.c
o.jp
150
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SOY
PEPT
IDE
CSP
HP
Kyo
wa
Supe
rSo
yK
YO
WA
HA
KK
OK
OG
YO
Co.
Ltd
.,Ja
pan
Not
spec
ified
Asi
a,E
aste
rnA
sia,
Japa
n
Ket
oba
r,L
emon
chif
fon
bar,
24g
prot
ein/
bar
65g,
soy
prot
ein
isol
ate,
hydr
olyz
edpr
otei
n
Lif
ese
rvic
essu
pple
men
tsR
educ
edca
rboh
ydra
tes
New
Jers
ey,U
.S.
Aqu
aso
ypr
otei
n10
0ad
ded
with
soy
pept
ides
67%
prot
ein
Mei
jiSe
ika
Kai
sha,
Toky
o,Ja
pan
Not
spec
ified
Cho
u-ku
Toky
o,Ja
pan
Die
tand
colla
gen
bar
15g
soy
prot
ein
16g
prot
ein/
45g
Mei
jiSe
ika
Kai
sha
Slim
dow
n,w
eigh
tco
ntro
lC
hou-
ku,T
okyo
,Jap
an
Wei
der
reco
ver
bar
with
4,00
0m
gso
ype
ptid
es,7
.7g
prot
ein/
58g
Mor
inag
a,To
kyo,
Japa
nE
nerg
yba
rM
inat
o-ku
Toky
o,Ja
pan
Soy
pept
ide
drin
kPe
ptei
n,5%
pept
ides
from
soy
prot
ein,
4g
prot
ein/
100
mL
Oso
thIn
ter
Lab
,Tha
iland
Not
spec
ified
Cho
nbur
i,T
haila
nd
Soy
pept
ide
drin
k,Pa
ptei
nO
sots
oa,T
haila
ndN
otsp
ecifi
edB
angk
ok,T
haila
nd
Soy
olig
opep
tides
Shan
dong
Duq
ing
Inc.
,C
hina
Not
spec
ified
Che
njiI
ndus
tria
lDis
tric
t,H
eze,
Shan
dong
,Chi
na
Soy
pept
ide
ener
gy-r
ecov
ery
beve
rage
s,8,
000
mg
ofso
ype
ptid
eTo
raku
/Soy
afar
m(K
obe)
,Ja
pan
Ene
rgy-
reco
very
beve
rage
prom
otes
ener
gyen
hanc
ing
tobo
dyan
dbr
ain
ww
w.th
e-pe
ptid
e.co
m
Ori
enta
lsty
leno
odle
sso
ype
ptid
es,
soyb
ean
sauc
e,9
gpr
otei
n/12
0g
Yak
ult,
Kor
eaN
otsp
ecifi
edSo
cho-
gu,S
eoul
,Sou
thK
orea
151
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152 Protein based ingredients
soy-fermented products. The activities of bioactive peptides have beendemonstrated, but their molecular mechanism of action is not yet clear. Fur-thermore, the investigations have been focused mainly on in vitro studiesand on animal models. Human clinical studies are limited or nonexisting.Bioactive peptides are released from protein by either food processingor GI digestion. Indirect evidence also suggests that these peptides canbe absorbed by the gastrointestinal system, thus exerting their action onspecific target organs. The effective plasma levels of bioactive peptidesare unknown and need to be determined. It is also important to discovernew peptides and their physiological functions in soy hydrolysates andfermented foods. The identification of these compounds will contributetoward a better understanding of the role of soy on obesity and the develop-ment of new functional ingredients with slimming characteristics. Morework is needed on processing technologies to make bioactive peptidesmore available to consumers.
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